Welcome and Introduction to IIMEC9 from Richard Simpson and Dr Ian Gibson

This year’s conference line-up was perhaps the most star-studded in the conference’s history, featuring no less than ten professors. As Richard Simpson said in his welcome address, “we’ve probably got our best conference yet in terms of the expertise on display here”. He also spoke positively about the ongoing networking enabled by the previous day’s Biomedical Research into ME Collaborative Meeting (BRMEC4), a regular pre-conference event enabling ME/CFS researchers from all over the world to share experience and bring in new ideas from outside the field of ME.

Perversely Dark

Simpson thanked the Irish ME Trust and Norges ME Forening – both members of the European ME Alliance – for their sponsorship of the conference, and then introduced a short trailer for a film about severe ME due to be released soon, called “Perversely Dark”. Film maker Pal Winsents and Fenome Film were given access to the ‘dark realms’ of ME/CFS patients Kristine and Bjornar, both of whom live in protective total darkness in two different locations near to Oslo. The result of six years of filming, Perversely Dark premiered in Oslo on May 12 and made the headlines on National TV that evening. The film will have English subtitles added.

‘Something of a Watershed’

Conference chair Dr Ian Gibson kept his opening remarks brief. Although the conference “grows year by year”, he cautioned that “we’re not there yet, there’s too many people suffering from ME”. Reflecting on the array of ideas and theories discussed at the previous day’s Collaborative Meeting, he suggested that “somewhere within all that cacophony…there’s an answer waiting to be picked up”. As usual, Gibson was positive and upbeat about the ME/CFS research scene, saying that the current state of ME/CFS research, in his opinion, is at “something of a watershed for us”, and speaking of the determination and spirit in the community and the “feeling that something’s going to happen”.

A Focus on Autoimmunity

After that brief introduction, it was on with the show…and the first three presentations – all delivered by distinguished Emeritus Professors from outside the field of ME research – set the scene by focusing on autoimmunity, introducing several themes that were echoed throughout the rest of the day. Professor Jonathan Edwards offered some helpful insights from his experience uncovering the autoimmune basis for Rheumatoid Arthritis; Professor Angela Vincent described the role of antibodies in a range of other autoimmune neurological diseases (in which her own contribution to the research has been vital); and Professor Jonas Blomberg told how XMRV had brought the field of ME research to his attention and presented some promising findings from his search for autoantibodies in ME/CFS patients. My series of articles on IIMEC9 begins with a closer look at these three presentations…

Lessons for ME Research from Rheumatoid Arthritis Research

Delivering the conference’s keynote address, Professor Jonathan Edwards (clinical trial advisor to Invest in ME on the UK Rituximab Clinical Trial, and a member of Phoenix Rising forums) explained that he had spent ‘pretty much his entire working life’ researching Rheumatoid Arthritis (RA), and he had thought that his career had finished in 2010 – until Dr Oystein Fluge suggested that he attend the Invest in ME conference. It struck Jonathan that here was a problem that ‘seemed somewhat familiar’ – and needed attention paying to it.

How does the current state of ME research look to an outsider, Edwards asked? To him it looks a bit like Rheumatoid Arthritis research looked in 1974. So does his experience in the progression of RA research since then offer any clues to the ME community? Edwards advised that two key tools are needed in order to ‘get a foothold’:

Reproducible biological findings to build an explanation of symptoms on.

A theoretical framework to build the explanation in.

As his conference abstract had noted, for ME these have been difficult to pin down, but “the recent finding of a response to Rituximab in ME patients indicates that at least a proportion of cases may have an autoimmune basis. This suggests that lessons learned in the study of conditions such as RA, which led to the initial use of Rituximab for autoimmunity, may provide clues for research into ME”.

Early Clues in Rheumatoid Arthritis

By 1994, for Rheumatoid Arthritis the following elements were known, but they really didn’t know how they fitted together:

a genetic predisposition with the HLA-DR4 serotype (HLA-DR is used by B cells and macrophages to talk to T cells)

an association with a history of smoking

most cases had Rheumatoid Factor and/or anti-citrulline autoantibodies (some patients had one, some had the other, some had both, and they weren’t sure what that meant)

inflammation was present, mediated by the TNF cytokine

The Random Factor

Introducing the answer that they came up with, Edwards reviewed the question of what factors cause disease. There are internal genetic factors, and environmental factors – but in RA, the search for infectious triggers had been in vain.

There’s a further factor, though, which is perhaps not so obvious – internal stochastic (random) processes. In the 1990s, Michael Neuberger’s work showed that there’s a system – the immune system – in which an enzyme randomly mutates your genes in order to create antibodies at random. This process is effectively similar to an ‘internally driven mutation’, and the origin of the ‘random’ process which can be a factor causing disease.

Toni’s Fitness Resort

Edwards then illustrated the nature of the autoimmune mechanism they found in RA by using a creative analogy, describing the rather unusual security system that Toni uses for the lockers at Toni’s Fitness Resort – “the perfect chillout for Rubovian oligarchs”. The Rubovians are notorious crooks, “but Toni doesn’t mind”.

In this system, Toni maintains 32 keys – provided by a security company – for lockers for the resort’s guests. Staff also have their own lockers. Toni keeps copies of all the keys in his own locker. He doesn’t bother to keep an index of which keys fit which locker, but instead he gives each Rubovian a key and tells them: “whichever key this fits, it’s yours”.

Unfortunately, Rubovians tend to lose their keys, so Toni needs a new box of keys every month. When the new keys arrive, Toni checks the provided keys against the staff lockers and destroys any that fit them, and then he hands out the rest of the keys to the guests. (These keys, I guess, are analagous to the receptor molecules carried by B and T cells and used to recognize specific targets. They are created effectively at random, checked against the staff lockers – the body’s own cells? – to make sure they don’t fit any of those, and then given to the guests / natural killer cells, with instructions to use them wherever they fit).

This system works fine for a couple of seasons, but one day Toni comes back to the resort to find all the lockers open, and everything gone. How did this happen? Well, Toni forgot to check the new sets of keys against his own locker, which contained copies of all the keys. Obviously some enterprising Rubovian received a key that happened to fit Toni’s locker, and opened it to discover a set of keys to all the other lockers.

What should we say was the cause of this disaster? Should we blame a particularly dishonest guest? That’s not really an answer: we already know that Rubovians are dishonest. Perhaps we should rather say that there was a weakness in the complex design of Toni’s security system? One might equally blame Toni’s random choice of a key. You can look at it whichever way you like, Edwards pointed out…

Solving the puzzle of RA

Edwards went on to outline how the solution was found to the puzzle presented by the clues known in the early 90s about RA. In 1993, Edwards observed that synovial intimal fibroblasts resemble bone marrow and follicular dendritic cells, and this prompted him to search for a story regarding B cell survival which could explain all the symptoms of Rheumatoid Arthritis.

The Rheumatoid Factor (RF) autoantibody, it turns out, is an antibody against the fragment crystallizable (Fc) region of IgG antibodies. This Fc region is the ‘tail’ of the Y-shaped IgG antibodies. Unlike the two ‘Fab’ arms, which contain the variable sections that define the specific target that the antibody can bind to, the Fc region is constant for all antibodies in a class and it mediates various physiological effects of antibodies. Since the Rheumatoid Factor can effectively attach to any IgG antibody on its Fc region, it functions a bit like a master key.

The discovery of the role of the FC gamma RIIIa receptor proved crucial in understanding the disease process in RA. It is expressed in many tissues, including synovial tissue, and its activation leads to the release of tumor necrosis factors (TNF), a group of cytokines that can cause cell death. This single effector mechanism, they realised, was able to explain all of the variety of RA symptoms. Now, Edwards noted, researchers are seeking to identify the single receptor mechanism that could explain the variety of ME/CFS symptoms…

The story of how the RA autoimmune process works is rather more complicated than this, though, and involves the subversion of complex feedback mechanisms in B cells. Aberrant signals sent back to parent B cells, and a discordance between T-cells and B-cells, result in the concept of self-perpetuating autoreactive B cells. These autoreactive B cells survive because both the T cell help pathway and the B cell receptor feedback signal are subverted.

Edwards summarised the key hypothesis that arose from these observations:

Most autoimmunity arises within the immune system by the chance production of ‘subversive’ B cells (actually, a gang of them talking to each other).

The logical treatment

Edwards explained that the logical treatment in this situation (an immune system that has been subverted by a gang of randomly-created B cells) is to remove all the current B cells and start again – and this is what Rituximab does. One might expect that this would be very dangerous, removing the body’s immune defences, but the fascinating thing is that we don’t actually need B cells all the time – they’re constantly being created and refreshed. In practice they did find that when using Rituximab as a treatment for Rheumatoid Arthritis, patients get better. Over the long term, Rituximab doesn’t remove the entire problem – it doesn’t remove all B cells, so that’s not surprising really – but with improved techniques they have been able to extend the period for which the treatment is effective.

Summary

Summing up, Edwards reviewed the lessons that can be learned from RA for ME:

the mechanism we are looking for may be subtle

genetic clues are gold dust

finding specific autoantibodies makes things easier, but evidence for a general immune mechanism may be just as good – Fluge and Mella’s finding can be just as good a piece of evidence as finding the actual autoantibody

there may be no specific infective trigger – but for some ME, maybe there is

identifying a cytokine pathway helps (it would be great if it was IL17 or interferon, but who knows?)

there will be several ‘ME’ diseases, just like there are in ‘RA’.

one can be surprised at what can be achieved

If you know what the problem is, Edwards asserted, you’re 80% of the way to getting the answer, and he would be very optimistic now that there are so many good people looking into this problem.

Questions

Noting the work of several ME researchers – in particular, Dr Chia – on enteroviral infection, Charles Shepherd asked whether it is safe to give Rituximab to people who may have (for example) persistent enteroviral infection? Edwards was reassuring: in practice, autoantibodies are depleted more than pathogen antibodies with Rituximab treatment, and by and large, infection has turned out not to be a major problem with Rituximab treatment. There are one or two viruses that may be a slight problem, and there may be a slight increase in herpes zoster, but nothing major. In general terms, reactivation of viruses is not a problem. We might worry if we knew that all ME patients had some particular persistent infection, but we already have evidence from Norway that this isn’t the case. Dr Fluge also commented to reassure on this point.

Finding Antibodies in Neurological Diseases

Professor Vincent explained that she was present at the conference due to her expertise in autoimmune neurological diseases, and not as an ME expert – it was a pleasure to be here though, and she had been learning a lot about ME that she didn’t know before.

Her presentation reviewed the hunt for antibodies in a variety of autoimmune neurological diseases, where antibodies were found to muscle or neuronal proteins in diseases of the muscles, nerves and brain. Were there similarities to be found in ME/CFS, she wondered? Millions of antibodies are present in the blood, mostly made completely randomly (the exception being when they are deliberately introduced via vaccines), and sometimes they attack parts of the body…

Myasthenia Gravis

Vincent’s fascinating and thought-provoking presentation included videos of patients with various autoimmune diseases. Myasthenia Gravis (MG) – the archetypal antibody-mediated disease – turned out to be caused by an autoimmune-mediated defect in the transmission between nerve and muscle. A specific antibody to a protein that’s important in the acetylcholine receptor affected the transfer of the signal from nerves to muscles, with the end result that sufferers couldn’t keep their eyes or mouths open, couldn’t smile…this was a very severe disease in the 1970s before it was understood. Then, in 1976, Lindstrom et al found the antibodies responsible. Removal of these antibodies by plasma exchange made the patients stronger, within a few days – but over time, the antibodies came back. Nowadays, steroids and other drugs are used to keep the antibodies down for as long as possible.

Vincent’s presentation highlighted some issues worth considering in the investigation of autoimmunity in ME/CFS. In Myasthenia Gravis, a late onset form (less common, and under-diagnosed) peaks mainly in males at age 65-75, whereas the overall peak onset of MG, at age 25-35, affects mainly females. So the genetics of these two forms are different, and similar heterogeneity is likely in ME/CFS. Vincent discovered that in a variant form of MG, the MuSK receptor is attacked. MuSK, like acetylcholine, performs an important function at the junction between nerves and muscles, so the autoimmune attack on it causes very similar symptoms to the attack on the acetylcholine receptor, via a different autoimmune mechanism. This form of MG is much more common in southern Europe, and extremely rare in northern Europe – though we still don’t know why. It would be most interesting to have some good epidemiological data on age of onset and regional variations in ME/CFS.

Acquired Neuromyotonia

The symptoms of Acquired Neuromyotonia suggest some possible overlaps and similarities with ME/CFS. It’s an autoimmune diseases affecting voltage-gated potassium channels (VGKC), causing spontaneous muscle activity due to hyper-excitability of peripheral nerves – twitching, cramps, etc. Clinical features include motor and sensory symptoms, pain is described as “aching, cramping, shooting, burning…”, and fatigue, exercise intolerance, internal buzzing, sweating, tinnitus and muscle spasms are also features of the illness.

Morvan’s Syndrome

Morvan’s Syndrome features disturbed circadian rhythms and symptoms relating to the peripheral, autonomic and central nervous systems. It’s a brain disease, caused by autoantibodies – which would previously have been considered quite impossible because the blood/brain barrier is supposed to protect against this. But nobody asks that question any more, Vincent said…

Morvan’s is a now-treatable form of limbic encephalitis, featuring memory loss, seizures and personality change. A comatose patient treated with Intravenous immunoglobulin (containing the pooled IgG antibodies extracted from the plasma of over 1000 donors), together with steroids, can now be seen sitting up and talking coherently.

The Morvan’s symptom of myoclonic jerks – appearing on video as a kind of nervous tick of the patient’s arms – would never have been noted as a neurological symptom without the discovery of the antibodies, Vincent said – again suggesting the possibility of a more promising future for ME/CFS if the autoimmune hypothesis can be confirmed.

Summary

In summing up, Vincent explained that there are a growing number of antibodies being identified, which attack various channels and receptors, in neurological diseases. Antibodies are now being detected in patients with other conditions including first episode psychosis, unexplained epilepsy, sleep disorders and pain. The presenting symptoms of these diseases do bear some striking similarities to many of the symptoms of ME/CFS, and as we’ve found with other diseases, once the specific autoantibodies have been found, effective treatments are quite possible.

Infection-induced autoimmunity in ME

Jonas Blomberg, from Sweden, introduced himself as a professor of clinical virology who has worked mostly on viral diseases, retroviruses and diagnostic tools. It was XMRV that got him hooked on the ME story, he explained – he had met a lot of patients while investigating XMRV and ME/CFS, and the disease seemed to him a most worthwhile subject for his group’s diagnostic efforts.

So his team has looked for antibodies in samples from ME/CFS patients, in the hopes of finding a clue to the reasons behind the disease. Their multiplex test is able to test for about 100 antibodies to over 900 viruses and bacteria at a time, so they tried to cover those viruses that have previously been associated with ME. Their results were surprising, and intriguing…

Patterns and Clues in ME

Before presenting the results of his search for antibodies in ME, Blomberg reviewed some patterns in ME that need to be explained, noting that there is often an ‘eliciting event’ (typically an initial infection) and pre-existing IBS is often present. One has to explain exhaustibility – both physical and mental – as well as pain, unrefreshing sleep, malaise, orthostatic hypotension, and irritable gut. But echoing a theme of the other presenters, he pointed out that an autoimmune condition can indeed affect many parts of the body: wherever the receptor targeted by the autoimmune antibody is present, adverse effects are possible.

A key clue, he said, is to look at co-morbid conditions that are common in ME/CFS patients – thyroid dysfunction, Orthostatic Intolerance, IBS and Fibromyalgia. But Blomberg’s starting point in pondering how autoimmunity could cause the symptoms of ME/CFS is to think about post-exertional malaise and exhaustibility in particular – and that makes him think about the mitochondria. There is already one known autoantibody, anti-pyruvate dehydrogenase, which is known to block mitochondrial function.

Thinking about symptoms of the autonomic nervous system (ANS), Blomberg pointed out that ‘accepted diseases’ such as Multiple Sclerosis, Guillain-Barre Syndrome and Narcolepsy do have correlations with viruses such as EBV, campylobacter and streptococcus. ME has been associated with initial infections from mycoplasma, chlamydia, giardia, EBV, CMV, and more…

Results ‘compatible with infection-induced autoimmunity’

Turning to his team’s search for antibodies in ME patients, Blomberg explained that their strategy had been to look for the antibody rather than for the microbe. They used a Suspension Multiplex Immuno Assay and tested for antibodies to viruses, bacteria and protozoa, finding positives on herpes viruses, parvovirus, polyomavirus and chlamydia pneumonia. They found that a subset of the ME patients they studied had antibodies to Heat Shock Protein 60 (HSP60), which is an ancient and highly conserved protein that occurs in mitochondria and in bacteria and is a major autoantigen. HSP60 functions as a mitochondrial chaperonin, responsible for the transport and folding of linear amino acid chains into their three-dimensional structure, so an antibody attacking it could potentially cause harm to the structure and function of mitochondria.

A potential biomarker

Having observed a tendency towards reactions to the whole HSP60 recombinant protein, they split it up and looked at reactions against overlapping peptides within HSP60. They found particularly strong reactions, on IgG and especially on IgM, to one particular portion of HSP60: Helix Loop I. Their findings were especially clear for the Chlamydia Pneumoniae heat shock protein. They then took the most selective peptide indicated by their initial study of 69 ME patients and 76 blood donors – a peptide from Chlamydia Pneumoniae HSP60 – and evaluated it in a further 61 ME and 399 non-ME samples (331 blood donors, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients). They detected IgM in 24% of the ME samples, but in only 1 of the 399 non-ME samples, at a high cutoff (p<0.0001). With this result succeeding even in discriminating ME as opposed to Multiple Sclerosis samples, they are hopeful that this finding could become a biomarker for at least a subset of ME/CFS.

The specific reaction to HSP60 which Blomberg’s team are observing is ‘relatively unique’, Blomberg noted. There are other antibodies known to bind to HSP60, but they do so in different places: in Blomberg’s ME studies, they find antibodies that bind to Helix Loop I.

Summarising his team’s findings, Blomberg repeated that in samples from ME patients they are seeing increased IgM reactions against peptides from Helix Loop I in HSP60, with marked cross-reactions between peptides from human and bacterial proteins. Blomberg’s final note was to emphasise that this does not mean that ME/CFS is caused by chlamydia pneumoniae infection.

Coming Up in Part 2…

After a short break, the rest of the morning’s presentations moved the focus from autoimmunity to the role of pathogens in ME/CFS.

Professor Mady Hornig updated us with the latest news from the Chronic Fatigue Initiative Pathogen Discovery and Pathogenesis Project at the Center for Infection and Immunity in Columbia University; Professor Carmen Schiebenbogen presented the findings of her team’s investigations of EBV infection in ME/CFS, with her evidence suggesting a deficient or dysregulated EMV-specific immune response in many ME/CFS patients; Professor Simon Carding moved the focus to the gut, presenting some fascinating facts and figures about the ‘second brain’ and ‘largest immune system in the body’, and introducing the 3-year IiME-funded PhD studentship to investigate the role of ‘leaky gut’ and intestinal microbiota in ME/CFS.

I’ll be taking a closer look at these three presentations in my next article, but while you’re waiting for that, you might like to review my article on last year’s Invest in ME Conference. Both Mady Hornig and Carmen Schiebenbogen presented at the 2013 conference, and Dr Ian Gibson announced the PhD studentship to look at gut bacteria in ME/CFS, so there’s plenty of useful background in my review of their presentations last year to help set the scene for the next article in this series…

First thing first I want to thank you Mark for reporting on the exquisite and one of a kind conference that is Invest in ME.

It's truly amazing what Pia and Richard Simpson have achieved with the help of all the volunteers and of course the real clinician, scientists and researchers that work tirelessly for all PWME, in just a few years (9 years that to many of us are a little eternity).

They are my true heroes!

Now I'll go finish reading, savoring, digesting, supporting and wishing for a better future for all PWME all over the world.

I wonder if the technology exists to detect and record every antibody within a person? Presumably if the antibodies are numerous enough to be causing disease, then they can be found throughout the body?

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